Pharmacokinetic modeling of multislice dynamic contrast-enhanced MRI in normal-healing radial fractures: A pilot study.

PURPOSE: To define the range of quantitative pharmacokinetic parameters in normal-healing bone with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI is an established technique for characterizing abnormal tissue microvasculature within solid tumors, but has also shown promise for assessing bone and bone marrow. MATERIALS AND METHODS: In this study ethical approval for eight patients was obtained. Inclusion criteria were an extra-articular distal radial fracture in patients aged 20-50 years which had united by 6 weeks in plaster cast. This was assessed by an experienced orthopedic surgeon. DCE-MRI was performed at 1.5T 6 weeks after initial injury. The transfer constant (K(trans) ), transfer rate (Kep ), and initial area under the curve (IAUC) values for the fracture site and adjacent marrow were obtained for each patient. RESULTS: The mean T1 , K(trans) , Kep , and IAUC at the fracture site were 1713 (standard deviation [SD] 645), 0.09 (SD 0.07), 0.17 (SD 0.17) and 4.9 (SD 4.4). The relative standard deviation (RSD) for the fracture site ranged from 0.38 to 0.97 and for the adjacent marrow ranged from 0.95-3.88. Within each patient the range of RSDs was 0.04-0.42 for T1 , 0.26-0.91 for K(trans) , 0.14-1.06 for Kep , and 0.35-0.96 for the IAUC. CONCLUSION: Pharmacokinetic measures of perfusion can be obtained from healing fractures using DCE-MRI with "excellent" intraclass correlation coefficients for inter- and intrarater reliability. The use of these perfusion parameters is limited by wide patient-to-patient variation and slice-to-slice variation within patients.

Percutaneous locking plates for fractures of the distal tibia: our experience and a review of the literature.

BACKGROUND: Distal tibial metaphyseal fractures pose many complexities. This study assessed the outcomes of distal tibial fractures treated with medial locking plates. METHODS: Eighteen patients were selected based on the fracture pattern and classified using the AO classification and stabilized with an AO medial tibial locking plate. Time to fracture union, complications, and outcomes were assessed with the American Orthopedic Foot and Ankle Society Ankle score at 12 months. RESULTS: Sixteen of the 18 patients achieved fracture union, with 1 patient lost to follow-up. Twelve fractures united within 24 weeks, with an average union time of 23.1 weeks. Three delayed unions, two at 28 weeks and one at 56 weeks. The average time to union was 32 weeks in the smokers and 15.3 weeks in the nonsmokers. Five of the 18 patients (27%) developed complications. One superficial wound infection, and one chronic wound infection, resulting in nonunion at 56 weeks, requiring revision. Two patients required plate removal, one after sustaining an open fracture at the proximal end of the plate 6 months after surgery (postfracture union)and the other for painful hardware. One patient had implant failure of three proximal diaphyseal locking screws at the screwhead/neck junction, but successful fracture union. The average American Orthopedic Foot and Ankle Society ankle score was 88.8 overall, and 92.1 in fractures that united within 24 weeks. CONCLUSIONS: Distal tibial locking plates have high fracture union rates, minimum soft tissue complications, and good functional outcomes. The literature shows similar fracture union and complication rates in locking and nonlocking plates.

Recombinant human bone morphogenetic protein-2: a randomized trial in open tibial fractures treated with reamed nail fixation.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) improves healing of open tibial fractures treated with unreamed intramedullary nail fixation. We evaluated the use of rhBMP-2 in the treatment of acute open tibial fractures treated with reamed intramedullary nail fixation. METHODS: Patients were randomly assigned (1:1) to receive the standard of care consisting of intramedullary nail fixation and routine soft-tissue management (the SOC group) or the standard of care plus an absorbable collagen sponge implant containing 1.5 mg/mL of rhBMP-2 (total, 12.0 mg) (the rhBMP-2/ACS group). Randomization was stratified by fracture severity. The absorbable collagen sponge was placed over the fracture at wound closure. The primary efficacy end point was the proportion of subjects with a healed fracture as demonstrated by radiographic and clinical assessment thirteen and twenty weeks after definitive wound closure. RESULTS: Two hundred and seventy-seven patients were randomized and were the subjects of the intent-to-treat analysis. Thirteen percent of the fractures were Gustilo-Anderson Type IIIB. The proportions of patients with fracture-healing were 60% and 48% at week 13 (p = 0.0541) and 68% and 67% at week 20 in the rhBMP-2/ACS and SOC groups, respectively. Twelve percent of the subjects underwent secondary procedures in each group; more invasive procedures (e.g., exchange nailing) accounted for 30% of the procedures in the rhBMP-2/ACS group and 57% in the SOC group (p = 0.1271). Infection was seen in twenty-seven (19%) of the patients in the rhBMP-2/ACS group and fifteen (11%) in the SOC group (p = 0.0645; difference in infection risk = 0.09 [95% confidence interval, 0.0 to 0.17]). The adverse event incidence was otherwise similar between the treatment groups. CONCLUSIONS: The healing of open tibial fractures treated with reamed intramedullary nail fixation was not significantly accelerated by the addition of an absorbable collagen sponge containing rhBMP-2.

Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies.

BACKGROUND: The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to improve the healing of open tibial shaft fractures has been the focus of two prospective clinical studies. The objective of the current study was to perform a subgroup analysis of the combined data from these studies. METHODS: Two prospective, randomized clinical studies were conducted. A total of 510 patients with open tibial fractures were randomized to receive the control treatment (intramedullary nail fixation and routine soft-tissue management) or the control treatment and an absorbable collagen sponge impregnated with one of two concentrations of rhBMP-2. The rhBMP-2 implant was placed over the fracture at the time of definitive wound closure. For the purpose of this analysis, only the control treatment and the Food and Drug Administration-approved concentration of rhBMP-2 (1.50 mg/mL) were compared. Patients who anticipated receiving planned bone-grafting as part of a staged treatment were excluded from enrollment. RESULTS: Fifty-nine trauma centers in twelve countries participated, and patients were followed for twelve months postoperatively. Two subgroups were analyzed: (1) the 131 patients with a Gustilo-Anderson type-IIIA or IIIB open tibial fracture and (2) the 113 patients treated with reamed intramedullary nailing. The first subgroup demonstrated significant improvements in the rhBMP-2 group, with fewer bone-grafting procedures (p = 0.0005), fewer patients requiring invasive secondary interventions (p = 0.0065), and a lower rate of infection (p = 0.0234), compared with the control group. The second subgroup analysis of fractures treated with reamed intramedullary nailing demonstrated no significant difference between the control and the rhBMP-2 groups. CONCLUSIONS: The addition of rhBMP-2 to the treatment of type-III open tibial fractures can significantly reduce the frequency of bone-grafting procedures and other secondary interventions. This analysis establishes the clinical efficacy of rhBMP-2 combined with an absorbable collagen sponge implant for the treatment of these severe fractures.

Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients.

BACKGROUND: The treatment of open fractures of the tibial shaft is often complicated by delayed union and nonunion. The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention. METHODS: In a prospective, randomized, controlled, single-blind study, 450 patients with an open tibial fracture were randomized to receive either the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]), the standard of care and an implant containing 0.75 mg/mL of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture at the time of definitive wound closure. Randomization was stratified by the severity of the open wound. The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively. RESULTS: Four hundred and twenty-one (94%) of the patients were available for the twelve-month follow-up. The 1.50-mg/mL rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary intervention because of delayed union; relative risk = 0.56; 95% confidence interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and significantly faster fracture-healing (p = 0.0022) than did the control patients. Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months (p = 0.0008). Compared with the control patients, those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fewer infections (in association with Gustilo-Anderson type-III injuries; p = 0.0219), and faster wound-healing (83% compared with 65% had wound-healing at six weeks; p =0.0010). CONCLUSIONS: The rhBMP-2 implant was safe and, when 1.50 mg/mL was used, significantly superior to the standard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures, accelerating fracture and wound-healing, and reducing the infection rate in patients with an open fracture of the tibia.